Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Volume 13, Issue 4 - 2026

Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation is an open access, peer-reviewed medical/scientific journal dedicated to publishing original research, reviews, and communications related to COPD. Following peer review and editorial acceptance, manuscripts are published online as quickly as possible as Articles in Press.  These accepted manuscripts are then aggregated into journal issues 6 times per year (January, March, May, July, September, and November) and made available to the COPD medical/research community at no charge, without a required subscription fee. The Journal is indexed by PubMed, PubMed Central, Scopus and Web of Science.

Original Research:

Association of Fractional Exhaled Nitric Oxide With Pulmonary Health and All-Cause Mortality in a Population Without Airflow Limitation

Shan Xiao, MD1* Xiang Wen, MD2* Wangli Qiu, MD3* Huajing Yang, MD2 Na Li, MD1 Chunxin Ye, MD1 Yan Shen, MD, PhD1

Author Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Shenzhen Longgang District Central Hospital, Shenzhen, China
  2. State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, People's Republic of China
  3. Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
*These authors contributed equally to this work.

Address correspondence to:

Yan Shen, MD, PhD
Department of Pulmonary and Critical Care Medicine
Shenzhen Longgang District Central Hospital
Shenzhen, China
Email: yanshen2008@163.com.

Abstract

Objectives: The association between fractional exhaled nitric oxide (FeNO) and airway inflammation is evident. However, the precise relationship of FeNO with pulmonary health and all-cause mortality among participants without airflow limitation remains undisclosed. We investigated the association of FeNO with respiratory symptoms, lung function, and all-cause mortality in this population.

Methods: Participants included in the 2007–2012 National Health and Nutrition Examination Survey cycles with complete questionnaire information, quality-controlled prebronchodilator spirometry data, acceptable FeNO data, and full follow-up records until December 31, 2019, were included. The skewed distribution of FeNO was addressed by applying natural logarithmic transformation. Multivariable linear regression, logistic regression, and Cox proportional-hazards regression analyses were used to investigate the relationship of FeNO with spirometry, respiratory symptoms, and all-cause mortality. Subgroup analyses were performed based on sex, age, body mass index, smoking status, and blood eosinophil count to validate the robustness of the results.

Results: The data of 5842 eligible participants were analyzed. After adjusting for confounding factors, for each 1-unit increment in natural logarithm (ln) (FeNO), the risk of chronic cough and wheezing decreased by 28% and 22%, respectively. Additionally, forced vital capacity increased by 27.9mL, and forced expiratory volume in 1 second increased by 27.8mL. During the average follow-up of 10 years, 255 participants experienced mortality. There was a nonlinear relationship between FeNO and all-cause mortality. Specifically, when ln (FeNO) was <2.6 (FeNO<13.5ppb), the hazard ratio was 0.45 (95% confidence interval 0.29–0.70; p<0.001). The subgroup analyses demonstrated consistent results.

Conclusions: Elevated FeNO was closely associated with fewer respiratory symptoms and improved lung function in a population without airflow limitation. A nonlinear relationship existed between FeNO and all-cause mortality, with mortality initially decreasing as FeNO increased, followed by stabilization.

Citation

Citation: Xiao S, Wen X, Qiu W, et al. Association of fractional exhaled nitric oxide with pulmonary health and all-cause mortality in a population without airflow limitation. Chronic Obstr Pulm Dis. 2026; 13(4): 328-339. doi: http://dx.doi.org/10.15326/jcopdf.2025.0718

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Reproductive Lifespan and Adult-Onset Bronchiectasis in U.S. Postmenopausal Women: An Investigation of the Women’s Health Initiative Cohort

Alexander I. Geyer, MD1 Shane J. Sacco, PhD2 Aladdin H. Shadyab, PhD3 Mark L. Metersky, MD2

Author Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, Zucker School of Medicine at Hofstra University / Northwell Health, New York, NY, United States
  2. Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut, United States
  3. Herbert Wertheim School of Public Health and Human Longevity Science and Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California San Diego, San Diego, California, United States

Address correspondence to:

Alexander I. Geyer, MD
Division of Pulmonary and Critical Care Medicine
Lenox Hill Hospital
Zucker School of Medicine at Hofstra University/Northwell Health
New York, NY
Email: ageyermd@gmail.com

Abstract

Background: While bronchiectasis disproportionately affects postmenopausal women, the role of reproductive factors in its pathogenesis is not well characterized. We hypothesized that a shorter reproductive lifespan is associated with higher risk of bronchiectasis.

Methods: We studied postmenopausal women in the Women’s Health Initiative study. The exposures included ages at menarche and menopause, and time between the 2 (reproductive lifespan). The outcome was the first incidence of bronchiectasis after Medicare enrollment, as reflected in the Medicare claims data. Incidence rates were calculated and a series of Cox proportional hazards models controlling for demographics, body mass index, smoking, oophorectomy, hormone therapy (HT), oral contraceptives, and comorbid conditions were created.

Results: Cumulative incidence of bronchiectasis in the cohort of 96,996 women was 2.7%. Shorter reproductive lifespan was associated with higher bronchiectasis risk (trend p=0.01). Women with the longest reproductive lifespan (≥40 years) were at 12% lower risk than those with the shortest reproductive lifespan (<30 years; adjusted approximate hazard ratio [aHR]=0.88 [95% confidence interval (CI): 0.77, 0.99]). HT modified this relationship (interaction p=0.04): shorter reproductive lifespan was associated with bronchiectasis risk only in the absence of HT (trend p=0.01). Without HT, women with the reproductive lifespans ≥40 years were at 22% lower risk of bronchiectasis than those with the reproductive lifespans <30 years (aHR=0.78 [95% CI: 0.62, 0.94]). The use of HT was associated with a 19% greater risk of bronchiectasis (p<0.01).

Interpretation: Longer reproductive lifespan is associated with reduced risk of bronchiectasis in postmenopausal women – but only in those without a history of HT use.

Citation

Citation: Geyer AI, Sacco SJ, Shadyab AH, Metersky ML. Reproductive lifespan and adult-onset bronchiectasis in U.S. postmenopausal women: an investigation of the Women’s Health Initiative cohort. Chronic Obstr Pulm Dis. 2026; 13(4): 316-327. doi: http://dx.doi.org/10.15326/jcopdf.2025.0740

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Association of Short-Term Pollen Exposure With Lung Function in COPD Patients

James P. Healy, MPH1 Wenli Ni, PhD1,2,3 Brent Coull, PhD4 Petros Koutrakis, PhD3 Andrew Synn, MD2 Nicholas Nassikas, MD1,2 Mary B. Rice, MD, MPH1,2,3

Author Affiliations

  1. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  2. Center for Climate, Health, and the Global Environment, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States
  3. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States
  4. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States

Address correspondence to:

Mary B. Rice, MD, MPH
Harvard T.H. Chan School of Public Health
665 Huntington Ave
Boston, MA 02115
Email: mbrice@hsph.harvard.edu

Abstract

Background: Environmental exposures such as air pollution are well established triggers for chronic obstructive pulmonary disease (COPD) exacerbation and impaired lung function. However, the role of aeroallergens, particularly pollen, has not been thoroughly examined in COPD, despite evidence that pollen inhalation can cause airway inflammation. We investigated whether short-term exposure to higher concentrations of ambient pollen is associated with changes in lung function in people with COPD.

Methods: Thirty COPD participants, contributing 1808 observations, were enrolled in the Study of Pollution and COPD Exacerbation and completed 4 clinic visits over one year while performing daily spirometry during four 30-day seasonal periods. Ambient total pollen was measured regionally. Associations of short-term pollen exposure (lag 1–7 days and cumulative 3- and 7-day concentrations) with forced expiratory volume in 1 second (FEV1) and forced vital capacity were assessed using distributed lag nonlinear models with a generalized additive mixed model. We tested if inflammatory biomarkers, inhaler medications, asthma history, and concurrent exposure ambient pollutants (nitrogen oxide, particulate matter diameter of 2.5 micrometers or less, ozone) modified associations between pollen exposure and lung function.

Results: Pollen exposure at lag 3 day was associated with a lower FEV1 (–5.5mL per interquartile range pollen increase; 95% confidence interval [CI]: –9.6, –1.3). Cumulative 3-day pollen exposure was similarly associated with a lower FEV1 (–4.9mL; 95% CI: –9.6, –0.2). Associations of pollen and FEV1 were greater in those with higher C-reactive protein and a diagnosis of asthma.

Conclusions: In this longitudinal study of people with COPD, higher short-term exposure to ambient pollen in the preceding 3 days was associated with a lower FEV1. Our findings suggest that aeroallergen exposure may worsen airflow obstruction in people with COPD.

Citation

Citation: Healy JP, Ni W, Coull B, et al. Association of short-term pollen exposure with lung function in COPD patients. Chronic Obstr Pulm Dis. 2026; 13(4): 284-292. doi: http://dx.doi.org/10.15326/jcopdf.2025.0735

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Gene Therapy: Knowledge, Attitudes, and Preferences Among Individuals with Alpha-1 Antitrypsin Deficiency

Kimberly E. Foil, MS1* Matthew M. Stern, PhD, MS1* Charlie Strange, MD2,3 Kristen E. Holm, PhD, MPH2,4 Robert A. Sandhaus, MD, PhD2,5 Gwen Hayden, BS3 Megan Lyle, BS, BSVS, OD6 Sarah N. Miller, RN, PhD7

Author Affiliations

  1. College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, United States
  2. AlphaNet, Inc., Coral Gables, Florida, United States
  3. Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
  4. Division of Neurology and Behavioral Health, National Jewish Health, Denver, Colorado, United States
  5. Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, United States
  6. Patient Representative
  7. College of Nursing, Medical University of South Carolina, Charleston, South Carolina, United States
*Co-first authors

Address correspondence to:

Kimberly Foil, MS
College of Health Professions
Medical University of South Carolina
Charleston, SC
Phone: (843) 792-6951
Email: foilk@musc.edu

Abstract

Background: Gene therapy is a promising approach to treating alpha-1 antitrypsin deficiency (AATD). This study is the first to assess knowledge, attitudes, and preferences of the alpha-1 patient community regarding gene therapies and gene therapy clinical trials.

Methods: An electronic survey collected demographic and health characteristics among the AlphaNet population and assessed knowledge, attitudes, and preferences related to gene therapy using multiple-choice, Likert-scale, and open-ended questions.

Results: Data were provided by 1112 participants (98% on augmentation therapy and 18% with liver disease). The number of correct responses to knowledge-based questions varied (range: 0–12; mean: 5.8/12 ± 3.1; median=6). While participants had generally positive perceptions of AATD gene therapy, attitudes and preferences differed between those at or above the knowledge median and those below. Those with higher knowledge were somewhat/very supportive of gene therapy research and development (56% versus 43%), somewhat/very willing to participate in a gene therapy clinical trial (70% versus 64%), and somewhat/very willing to receive a U.S. Food and Drug Administration-approved gene therapy (87% versus 74%) (all p< 0.001). A gene therapy capable of targeting both liver and lung disease was preferred, along with therapies that require the least frequent re-dosing.

Conclusions: This study identifies knowledge, attitudes, and opportunities to correct misconceptions related to gene therapy in the alpha-1 community. Participants indicated desire for additional education, and increased knowledge was associated with more positive attitudes towards gene therapy. Thus, the benefit of educational efforts and materials may extend beyond the individual learner and also facilitate trial enrollment and therapy uptake.

Citation

Citation: Foil KE, Stern MM, Strange C, et al. Gene therapy: knowledge, attitudes, and preferences among individuals with alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2026; 13(4): 293-304. doi: http://dx.doi.org/10.15326/jcopdf.2026.0784

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Who Enrolls After Referral to Virtual Pulmonary Rehabilitation? A Descriptive Comparison

Emily A. Schultz, BS1 Madeleine Frank, MHSA2 Sara L. Eppler, MPH1 Melissa Dymock, MBA2 Robin N. Kamal, MD, MBA, MS1 Julia Maheshwari, MD3 Lauren E. Eggert, MD3

Author Affiliations

  1. VOICES Health Policy Research Center, Standford University, Stanford, California, United States
  2. Department of Medicine, Standford Health Care, Standford, California, United States
  3. Division of Pulmonary, Allergy, Critical Care Medicine, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States

Address correspondence to:

Lauren E. Eggert, MD
Division of Pulmonary, Allergy, Critical Care Medicine, and Sleep Medicine
Department of Medicine
University of California San Francisco
San Francisco, California
Email: lauren.eggert@ucsf.edu

Abstract

Background: Multidisciplinary management of chronic obstructive pulmonary disease (COPD) that combines pharmacotherapy, patient education, and pulmonary rehabilitation (PR) is recommended to optimize outcomes. Virtual pulmonary rehabilitation (VPR) offers a novel approach to expanding access to care by addressing geographic barriers.

Methods: We conducted a retrospective cohort study involving patients with COPD who were referred to a VPR program from the pulmonary clinic of a single academic center. Demographic information was collected. The Social Vulnerability Index (SVI) was determined and the mean distance to the nearest in-person PR program. The primary objective was to describe the characteristics of patients referred to VPR who enrolled in the program compared with those who did not. The secondary objectives were to understand reasons patients choose not to enroll in VPR and to evaluate changes in clinical outcomes before and after participation in the program, with comparisons across SVI.

Results: A total of 278 patients were referred, of whom 63 (22.7%) either completed or were actively participating in the program. Of the patients referred, 23 (8.3%) were ineligible, and another 45 (16.2%) declined enrollment. The average age of enrolled patients was 76.7 (8.4) years, and most patients were female (N=38, 60.3%). The average SVI was 0.53 (medium social vulnerability). The average distance to an in-person PR center was 12.6 miles. There were no significant differences in SVI, distance to PR center, language, or race between enrolled and nonenrolled patients.

Conclusions: VPR may serve as an effective, accessible option for patients with COPD to improve functional and patient-centered outcomes. However, despite mitigating geographic barriers through VPR, obstacles to expanding PR program enrollment persist.

Citation

Citation: Schultz EA, Frank M, Eppler SL, et al. Who enrolls after referral to virtual pulmonary rehabilitation? A descriptive comparison. Chronic Obstr Pulm Dis. 2026; 13(4): 275-283. doi: http://dx.doi.org/10.15326/jcopdf.2025.0729

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Borderline Forced Expiratory Volume in 1 Second to Forced Vital Capacity and Low Forced Expiratory Volume in 1 Second Predict Disease Progression in High-Risk Populations With COPD

Xingyao Tang, MD1,2 Wei Li, MD2 Jieping Lei, PhD2,3 Hongtao Niu, MD2 Minghui Shi, MD1,2 Jisong Yan, MD2,4 Yaodie Peng, MD2,5 Yanan Cui, MD2 Tingting Huang, MD2 Yong Li, BS2 Jun Pan, MS6 Chunyu Zhang, PhD6 Cunbo Jia, MS6 Xu Chu, MD2 Ting Yang, MD, PhD1,2 Ke Huang, MD1,2

Author Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship School of Clinical Medicine, Capital Medical University, Beijing, China
  2. National Center for Respiratory Diseases; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
  3. Data and Project Management Unit, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
  4. Chinese Academy of Medical Sciences and Peking Union Medical College, China-Japan Friendship Hospital, Beijing, China
  5. Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
  6. General Office, China-Japan Friendship Hospital, Beijing, China

Address correspondence to:

Ke Huang, MD
Beijing, China
Phone: +86-010-84206273
Email: huangke_zryy@163.com

 

Ting Yang, MD, PhD
Beijing, China
Phone: +86-010-84206273
Email: zryyyangting@163.com

 

Xu Chu, MD
Beijing, China
Phone: +86-010-84206273
Email: chuxu0711@126.com

Abstract

Background and objectives: The ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), and the proportion of FEV1 percentage predicted are used to diagnose and determine disease severity in chronic obstructive pulmonary disease (COPD). This study investigated the prognostic capabilities of borderline FEV1 to FVC and low FEV1 on disease progression among a population at high risk for COPD.

Methods: This study utilized 2-year follow-up data from the National COPD Screening Program. Participants were divided into 4 groups according to FEV1 to FVC and FEV1: normal ratio with normal FEV1, borderline ratio with normal FEV1, normal ratio with low FEV1, and borderline ratio with low FEV1. The outcomes were FEV1 decline and progression to airway obstruction.

Results: This study included a total of 2969 patients at high risk for COPD. Compared with the normal ratio with normal FEV1 group, the borderline ratio with normal FEV1 (adjusted odds ratio [OR]=1.81, 95% confidence interval [CI]: 1.34 to 2.44) and borderline ratio with low FEV1 (adjusted OR=2.32, 95%CI: 1.46 to 3.69) groups showed higher risks of developing airway obstruction, while the normal ratio with low FEV1 group showed no significant change in risk (adjusted OR=1.31, 95% CI: 0.83 to 2.07). Further, the findings also were proven true in the general population with longer follow years by using data from the U.K. Biobank (the borderline ratio with normal FEV1 group: adjusted hazard ratio [HR] = 2.92, 95% CI: 2.28 to 3.74; and borderline ratio with low FEV1 group: adjusted HR = 4.53, 95% CI: 3.21 to 6.38).

Conclusion: Participants with borderline FEV1/FVC have a higher risk of developing airway obstruction, regardless of a decline in FEV1.

Citation

Citation: Tang X, Li W, Lei J, et al. Borderline forced expiratory volume in 1 second to forced vital capacity and low forced expiratory volume in 1 second predict disease progression in high-risk populations with COPD. Chronic Obstr Pulm Dis. 2026; 13(4): 262-274. doi: http://dx.doi.org/10.15326/jcopdf.2025.0700

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An Interpretable Multidimensional Acoustic Physiology Map for COPD Using Digital Lung Sounds

İhsan Topaloğlu, MD1 Çağrı Atasoy, MD1 Aylin Bayram, MD1 Gülfem Özduygu, MD2 Mutlu Onur Güçsav, MD3 Damla Serçe Unat, MD3 Soner Kına, MD4 Yekta Bektaş, MD4 Furkan Halifeoğlu, MD4 Arif Metehan Yıldız, PhD5

Author Affiliations

  1. Department of Pulmonology, Faculty of Medicine, Kafkas University, Kars, Turkey
  2. Department of Pulmonology, Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, University of Health Science, Istanbul, Turkey
  3. Department of Pulmonology, Çiğli Regional Training and Research Hospital, İzmir Bakırçay University, İzmir, Turkey
  4. Department of Anesthesiology and Reanimation, Faculty of Medicine, Kafkas University, Kars, Turkey
  5. Department of Computer Engineering, Faculty of Engineering, Ardahan University, Ardahan, Turkey

Address correspondence to:

İhsan Topaloğlu, MD
Department of Pulmonology
Faculty of Medicine
Kafkas University
Kars, Turkey
Phone: +90 530 122 63 11
Email: ras-topal@hotmail.com

Abstract

Background: Lung sound analysis may capture chronic obstructive pulmonary disease (COPD) related physiology, but many methods are hard to interpret clinically. We developed a multidimensional acoustic physiology map using 4 indices from digital lung sounds: median respiratory frequency (MRF), long-term energy index (LTEI), subharmonic index (SubH), and harmonicity deviation index (HDI).

Methods: In this single-center retrospective study, 235 adults were classified as Healthy (n=62), Stable COPD (n=85), or COPD Exacerbation (n=88). We analyzed 1403 posterior thoracic 15-second recordings. Between-group differences in the 4 indices were tested with the Kruskal–Wallis test; when significant, Dunn posthoc pairwise comparisons were performed with Holm adjustment. Multidimensional separation was evaluated in the z-scored 4-index space using principal component analysis and permutational multivariate analysis of variance. All tests were 2-sided with a P-value < 0.05 considered significant.

Results: Overall group differences were significant for MRF (P-value =1.36×10⁻⁵), SubH (P-value =3.29×10⁻⁶), and HDI (P-value =4.74×10⁻⁸), whereas LTEI did not show a statistically significant overall effect (P-value =0.086). Posthoc analyses indicated that MRF and SubH primarily separated Stable COPD from both Healthy and COPD Exacerbation, while HDI primarily separated COPD Exacerbation from Healthy and Stable COPD. Group distributions were visualized with triangular heatmaps and summarized in a 3-axis model.

Conclusions: Complementary acoustic indices reflect distinct domains of COPD-related sound generation and transmission. Although standalone classification performance was limited, the proposed map provides an interpretable framework for digital auscultation phenotyping and future composite scoring

Citation

Citation: Topaloğlu İ, Atasoy Ç, Bayram A, et al. An interpretable multidimensional acoustic physiology map for COPD using digital lung sounds. Chronic Obstr Pulm Dis. 2026; 13(4): 305-315. doi: http://dx.doi.org/10.15326/jcopdf.2025.0746

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